Incretin mimetics as a novel therapeutic option for hepatic steatosis.

BACKGROUND: Fat accumulation in the liver or non-alcoholic fatty liver disease (NAFLD) is regarded as a key pathogenic factor and component of the metabolic syndrome. It was reported that administration of the incretin mimetic exenatide reversed hepatic steatosis in an obese mouse model. We had the opportunity to study the effect of additional exenatide administration on liver fat content in a patient with type 2 diabetes. CASE REPORT: A 59-year-old male with poorly controlled type 2 diabetes was treated with exenatide in addition to metformin monotherapy. Following 44 weeks of exenatide therapy, mean the liver fat measured by liver spectroscopy declined from 15.8% to 4.3%. This dramatic decrease in liver fat was accompanied by significant beneficial changes in several cardiovascular disease risk factors and improvement of all liver enzymes, in particular alanine aminotransferase, the most important marker of liver steatosis. CONCLUSION: This case report suggests that the incretin mimetic exenatide decreases hepatic fat accumulation and may play a role in the future treatment of NAFLD, and the associated insulin resistance and cardiovascular risk factors in an ever-growing high-risk population.     

Progression-free interval in ovarian cancer and predictive value of an ex vivo chemoresponse assay

The study objective was to determine the effectiveness of a phenotypic chemoresponse assay in predicting response to chemotherapy measured by progression-free interval (PFI) in a retrospective series of ovarian cancer patients whose tumor specimens had been tested with the ChemoFx assay. A statistically significant correlation between assay prediction of response and PFI was observed in 256 cases with an exact or partial match between drug(s) assayed and received. In 135 cases with an exact match, the hazard ratio for progression of the resistant group was 2.9 (confidence interval [CI]: 1.4-6.3; P < 0.01) compared to the sensitive group and 1.7 (CI: 1.2-2.5) for the intermediate compared to the sensitive group. The median PFI for patients treated with drugs assayed as resistant was 9 months, 14 months for those with drugs assayed as intermediately sensitive, and PFI had not been achieved for those with drugs assayed as sensitive. These data indicate that the ChemoFx assay is predictive of PFI in ovarian cancer. As the majority of ovarian cancers display different degrees of response to different chemotherapy agents ex vivo, the incorporation of assay information into treatment selection has the potential to improve clinical outcomes in ovarian cancer patients.     

Dysfunction of the pupillary light reflex following migraine headache

Using pupillometry and sympathetic skin responses we compared the changes in local and systemic autonomic function within one week of a migraine attack. We investigated whether the measurement of the pupillary light reflex provides further information on the pathophysiology of migraine. Forty-two migraine patients and forty-two healthy age-matched controls were included. The parameters that were measured were the amplitude of the pupillary light reflex, the pupil size at the beginning of the measurement, the latency, the velocity of constriction and the velocity at the end of the dilatation. The average pupil size was 6.43 mm in the migraine group and 6.7 mm in the control group (p < 0.01). Reduced velocity of constriction and smaller amplitude of constriction in migraine patients within two days of an attack were signs of a parasympathetic dysfunction (p < 0.05). The sympathetic skin response did not differ significantly between migraine sufferers and controls. These findings indicate that both parasympathetic and sympathetic nerves supplying the eye are involved in migraine headache presumably due to effects on the pericarotid sympathetic fibers and involvement of trigeminal-parasympathetic reflexes. Received: 24 July 2001, Accepted: 16 July 2002 Correspondence to K. Schepelmann, M. D.     

Cutaneous postural vasoconstriction is modified by exogenous but not endogenous female hormones in young women

Previously reported attenuation of skin postural vasoconstriction in women during the luteal menstrual cycle phase may be due to a progesterone-mediated decrease in myogenic or veno-arteriolar (VAR) mechanisms. Skin perfusion was measured in the shin and foot dorsum by Laser Doppler Fluxometry during leg dependency that increased vascular transmural pressure below (myogenic constriction only) and above (myogenic and VAR) the 25 mmHg threshold for activation of the VAR, and during venous distension to activate the VAR alone (cuff inflation to 50 mmHg). In six young women with normal menstrual cycles, vasoconstrictor responses to all interventions did not differ between days 7–13 (follicular) and 18–23 (luteal) of the normal menstrual cycle when progesterone levels were low and at their peak respectively. In eight women taking combined oral contraceptives (OC) and tested during pill consumption days, reductions in foot skin perfusion were smaller (P = 0.05) than in the luteal phase of the normal cycle for leg dependency below (−36.9 ± 5.2% OC vs. −52.5 ± 7.8% luteal, mean ± S.E.M.) and above (−43.7 ± 3.4% OC vs. −55.1 ± 4.8% luteal) the VAR threshold, and for venous distension (−53.1 ± 2.6% OC vs. 66.4 ± 5.5% luteal). In women with normal menstrual cycles, impaired postural vasoconstriction may be confined to those who experience pre-menstrual symptoms rather than a direct effect of endogenous hormones. Reduced vasoconstriction in the dependent foot during OC use is consistent with the known vasodilator action of exogenous hormones and its long-term effects     

转录因子Egr-1在失血性休克复苏后肝脏损伤中的作用

目的研究转录因子Egr-1在失血性休克复苏（HS/R）后肝脏损伤中的作用.方法利用Egr-1野生型（WT）和基因封闭型（KO）小鼠复制失血性休克复苏模型.取肝组织,RT-PCR法测定肝组织中TNF-α、IL-6、G-CSF、ICAM-1 mRNA的表达变化.通过检测肝组织中MPO的含量、血清ALT水平和组织学检查,评估肝脏炎症细胞浸润和损伤程度.结果失血性休克2.5 h＋复苏4 h后,Egr-1 KO小鼠肝组织中TNF-α、IL-6、G-CSF、ICAM-1 mRNA的表达水平明显低于Egr-1WT组;Egr-1 KO组失血性休克复苏后肝组织炎性浸润和损伤程度减轻,表现为血清ALT水平低,肝组织中MPO含量低,病理损伤轻.结论本实验结果表明转录因子Egr-1参与了失血性休克复苏后肝脏炎症反应基因表达的调节,在失血性休克复苏后的肝脏损伤中起一定的作用.     

多分类有序反应变量logistic回归应用条件的检验

目的 对多分类有序反应变量logistic回归的应用条件寻求科学合理的检验方法。方法 使用卡方分布的理论，SAS软件及抽样调查方法。结果 设计出多分类有序反应变量logistic回归应用条件的卡方检验方法，推导出反应变量取各水平的概率计算公式及卡方检验中理论值、自由度的计算公式，并在作者主持的国家医师资格临床实践技能考试研究中取得了成功效果。结论 多分类有序反应变量logistic回归得到完善和补充，具有较大的理论和实际意义。     

Functional magnetic resonance imaging based on changes in vascular space occupancy.

During brain activation, local control of oxygen delivery is facilitated through microvascular dilatation and constriction. A new functional MRI (fMRI) methodology is reported that is sensitive to these microvascular adjustments. This contrast is accomplished by eliminating the blood signal in a manner that is independent of blood oxygenation and flow. As a consequence, changes in cerebral blood volume (CBV) can be assessed through changes in the remaining extravascular water signal (i.e., that of parenchymal tissue) without need for exogenous contrast agents or any other invasive procedures. The feasibility of this vascular space occupancy (VASO)-dependent functional MRI (fMRI) approach is demonstrated for visual stimulation, breath-hold (hypercapnia), and hyperventilation (hypocapnia). During visual stimulation and breath-hold, the VASO signal shows an inverse correlation with the stimulus paradigm, consistent with local vasodilatation. This effect is reversed during hyperventilation. Comparison of the hemodynamic responses of VASO-fMRI, cerebral blood flow (CBF)-based fMRI, and blood oxygenation level-dependent (BOLD) fMRI indicates both arteriolar and venular temporal characteristics in VASO. The effect of changes in water exchange rate and partial volume contamination with CSF were calculated to be negligible. At the commonly-used fMRI resolution of 3.75 x 3.75 x 5 mm(3), the contrast-to-noise-ratio (CNR) of VASO-fMRI was comparable to that of CBF-based fMRI, but a factor of 3 lower than for BOLD-fMRI. Arguments supporting a better gray matter localization for the VASO-fMRI approach compared to BOLD are provided.     

Recombinant human erythropoietin in the treatment of cancer-related anaemia

Abstract: The efficacy and safety of recombinant human erythropoietin (rhEPO) were tested when given subcutaneously (s.c.) in an escalating dose of 2000–10,000 units (U) daily in 60 patients with cancer-related anaemia (CRA). A positive response, defined as an increase in haemoglobin more than 2 g/dl and independence of blood transfusions, was observed in 23 of 48 evaluable patients (48%) within a median of 8 wk. In detail, rhEPO corrected anaemia in 11 of 14 patients (79%) with malignant lymphoma, in 8 of 15 patients (53%) with multiple myeloma and in 4 of 10 patients (40%) with a solid tumour. The median dose of rhEPO in successful cases was 5000 U daily. Four patients with agnogenic myeloid metaplasia and 5 with myelodysplastic disorder failed to respond to rhEPO. No patient had any severe side effects. Pretreatment serum erythropoietin levels appeared to be a weak predictor for response to rhEPO treatment. In conclusion, rhEPO seems to be safe and effective in correcting CRA in certain groups of patients.     

The Effect of Quisqualic Acid-Induced Lesions of the Nucleus Basalis Magnocellularis on Latent Inhibition

Latent inhibition (LI) is a reduction in the rate of acquisition of a Pavlovian conditioned response that results from prior nonreinforced preexposure to a conditioned stimulus (CS). LI has been suggested to reflect the operation of mechanisms involved in stimulus selection for subsequent cognitive processing. The present experiment was conducted to assess the effect of bilateral lesions of the nucleus basalis magnocellularis (NBM) on LI employing a conditioned emotional response paradigm. Bilateral lesions of the NBM were produced by administration of 0.12 M quisqualic acid and resulted in decreased cortical acetylcholinesterase staining, as well as a 40% reduction in cortical choline acetyltransferase activity. Following lever press training, preexposed animals received 40 presentations of a 60-s tone CS. Nonpreexposed animals received no tone presentations. Acquisition of conditioned suppression was then assessed over the course of 4 tone-shock (0.6 mA, 0.5 s) pairings. Control, preexposed animals displayed a retarded rate of acquisition in comparison to nonpreexposed controls, thereby demonstrating that the parameters used in the present experiment produced LI. In contrast, lesioned animals preexposed to the CS acquired conditioned suppression as readily as non-preexposed lesioned animals. However, the acquisition of conditioned suppression in both lesioned groups was found to be similar to that displayed in the preexposed control group. This pattern of results was interpreted as being attributable to a lesion-induced impairment in the ability to maintain stimulus processing, rather than a deficit in the ability to filter a stimulus. Copyright © 1996 Elsevier Science Inc.     

Behavioral conditioning of endotoxin-induced plasma iron alterations

The cascade of physiologic mechanisms in response to infection, the acute-phase response, is recognized as playing a major role in host defence. One such response is the hypoferremia that is consistently reported to occur during bacterial infection. This study aimed to determine whether the alterations in plasma iron were conditionable using the conditioned taste aversion (CTA) paradigm. The regime involved the pairing of a novel-tasting saccharin solution with bacterial endotoxin. Seven days after the initial pairing of these stimuli (the test day), the saccharin solution was represented. Animals exposed to this condition displayed a significant reduction in the level of plasma iron. Animals treated with an intraperitoneal dose of 400 μg/Kg lipopolysaccharide (LPS) displayed lower conditioned iron levels than rats infused with 100 μg/Kg LPS; however, this difference was not significant. These results showed that in addition to other acute-phase responses (fever and anorexia), plasma iron alterations are able to be manipulated through behavioral manipulations.